The discovery of compounds capable of preventing cocaine's harmful properties with minimal physiological effects is a promising area of research. Cocaine abuse is intensively studied;however, there are no proven pharmacological treatments for cocaine addiction or overdose. Planarian flatworms are a promising animal model to study the behavioral effects of cocaine. In evolutionary terms, planarians are the first example of organisms displaying a well-defined brain, which shares many structural similarities with the vertebrate nervous system. Planarians can exhibit behavioral symptoms consistent with cocaine "withdrawal" and show morphological changes in their nervous system directly associated with acute and chronic cocaine exposure. Planaria is a classically "underused" animal model in pharmacological research. Working with this organism has several distinct advantages. They are commercially available at very low cost and are very easily kept in the laboratory. The natural cyclic sesquiterpene lactone (SL), parthenolide and related analogs prevent the expression of behavioral effects induced by acute cocaine administration to the flatworm planaria. Additionally, parthenolide prevents the induction of withdrawal-like behaviors in response to chronic cocaine exposure in the same organism. The main purpose of this project is to screen additional SL analogs for their ability to antagonize cocaine effects in planarians. The proposed experiments will provide information pointing at a pharmacophore (the set of structural features that a compound must possess to exhibit a certain activity) for the parthenolide-like family of compounds ability to reverse the cocaine-induced behaviors in planarians. This pharmacophore will help to discover novel compounds capable to act as anti-cocaine agents. Any information about the interaction of parthenolide-like compounds and cocaine in planaria will be useful in the search for compounds capable of acting as anti-cocaine agents in a variety of organisms, including humans. The long-term goal of our research is to discover and develop compounds capable to prevent or alleviate abused drugs effects in humans. PUBLIC HEALTH RELEVANCE: Cocaine abuse is a significant public health problem. To date, no compounds exist that can alleviate the toxic or behavioral effects of cocaine. The information that will be obtained from the proposed experiments will provide novel directions in the search for substances that may serve as anti-cocaine agents.